title: Membrane cholesterol as a mediator of the neuroprotective effects of estrogens.
abstract: Alzheimer's disease (AD), the most common neurodegenerative disease associated with aging, is still an incurable condition. Although in vitro evidence strongly indicates that estrogens exert neurotrophic and neuroprotective effects, the role of this class of hormones in the treatment of AD is still a debated issue. In 2000 a new gene, named seladin-1 (for SELective Alzheimer's Disease INdicator-1), was identified and found to be down regulated in vulnerable brain regions in AD. Seladin-1 was considered a novel neuroprotective factor, because of its anti-apoptotic activity. Subsequently, it was demonstrated that seladin-1 has also enzymatic activity [3-β-hydroxysterol delta-24-reductase, (DHCR24)], which catalyzes the synthesis of cholesterol from desmosterol. The amount of membrane cholesterol may play an important role both in protecting neuronal cells against toxic insults and in inhibiting the production of β-amyloid. We demonstrated that seladin-1 overexpression increases the amount of membrane cholesterol and induces resistance against β-amyloid aggregates in neuroblastoma cells, whereas a specific inhibitor of DHCR24 increased cell vulnerability. We also hypothesized that seladin-1 might be a mediator of the neuroprotective effects of estrogens. We first demonstrated that, in human fetal neuroepithelial cells (FNC), 17β-estradiol, raloxifene, and tamoxifen exert protective effects against β-amyloid toxicity and oxidative stress. In addition, these molecules significantly increased the expression of seladin-1 and the amount of cell cholesterol. Then, we showed that, upon seladin-1 silencing, the protective effects of estrogens were abolished, thus indicating this factor as a fundamental mediator of estrogen-mediated neuroprotection, at least in FNC cells. Furthermore, we detected the presence of functionally active half-palindromic estrogen responsive elements upstream the coding region of the seladin-1 gene. Overall, our results indicate that seladin-1 may be viewed as a multi-faceted protein, which conjugates both the neuroprotective properties of estrogens and the important functions of cholesterol in maintaining brain homeostasis. This article is part of a Special Issue entitled: Neuroactive Steroids: Focus on Human Brain.
authors.affiliation: Department of Clinical Physiopathology, Endocrine Unit, Center for Research, Transfer and High Education on Chronic, Inflammatory, Degenerative and Neoplastic Disorders for the Development of Novel Therapies (DENOThe), University of Florence, Florence, Italy. a.peri@dfc.unifi.it
authors.forename: A
authors.initials: A
authors.lastname: Peri
authors.forename: S
authors.initials: S
authors.lastname: Benvenuti
authors.forename: P
authors.initials: P
authors.lastname: Luciani
authors.forename: C
authors.initials: C
authors.lastname: Deledda
authors.forename: I
authors.initials: I
authors.lastname: Cellai
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000166:cytology; D002462:Cell Membrane / Q000187:drug effects* / Q000201:enzymology; D002784:Cholesterol / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology*; D006801:Humans; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000378:metabolism*
chemical_list: D004967:Estrogens; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D002784:Cholesterol; D044925:Oxidoreductases Acting on CH-CH Group Donors; C499055:DHCR24 protein, human